Kiyoshi Tomioka

Copper-Catalyzed Asymmetric Alkylation of Imines with Dialkylzinc and Related Reactions

The catalytic asymmetric addition reactions of organometallic reagents to CdN double bonds of imines are fundamentally important processes, which provide convenient and versatile routes to optically active amines bearing a stereogenic center at the R-position. Optically active R-branched amines are important chiral building blocks, and are abundantly present in biologically active compounds, such as methoxyphenamine (a 2-adrenergic antagonist for treatment of asthma), rivastigmine (an AcCh esterase inhibitor for treatment of Alzheimer’s disease), tamsulosin (a selective R1-adrenergic antagonist to improve urinary trouble due to prostatic hyperplasia), and repaglinide (a blocker of ATP-dependent K channels in cells used as a hypoglycemic agent) (Figure 1). Asymmetric addition to CdN double bonds has been achieved based on the use of a chiral auxiliaries or chiral ligands. In 1982, Takahashi and co-workers reported the pioneering work of a chiral auxiliary-controlled asymmetric addition of organolithium reagents to imines 1 derived from aldehydes and valinol or phenylglycinol (Scheme 1). The chiral auxiliary strategy is still an important technology from a practical point of view because separation of the diastereomeric products prior to cleavage of the chiral auxiliary provides enantiomerically pure products. In the past two decades, the asymmetric additions of organometallic reagents to the CdN double bonds of imines in the presence of a stoichiometric or catalytic amount of a chiral ligand have been developed as a new technology for the synthesis of optically active amines, including alkaloids. The ligandinduced enantioselective synthesis has the potential for direct recovery and reuse of the unchanged chiral ligands. In 1990, Tomioka and co-workers reported the first chiral ligandcontrolled asymmetric addition reaction of organometallic compounds to CdN double bonds of imines with organolithium reagents activated by a chiral amino ether ligand 5 (Scheme 2). Even with 5 mol % of ligand 5, enantiomerically enriched amine 6 was produced, though with moderate ee, opening up the door to catalytic asymmetric addition reactions of organometallic reagents to a CdN double bond of an imine. Denmark and co-workers also showed the excellent ability of asymmetric induction of (-)-sparteine and bisoxazoline ligands and the catalytic use of these ligands for addition of organolithium reagents to imines (Scheme 3). In 1992, Soai and co-workers reported the first catalytic asymmetric addition reaction of a dialkylzinc reagent to a CdN double bond. In the presence of chiral amino alcohol 11, addition of dialkylzinc reagents to N-(diphenylphosphinoyl) imines proceeded with high enantioselectivity (Scheme 4). Surprisingly good enantioselectivity was observed even with 10 mol % of the amino alcohol, although the chemical yield was not satisfactory. Since these early examples, considerable energetic approaches toward the catalytic asymmetric addition of organometallic reagents to CdN double bonds of imines have appeared. Among these, chiral π-allylpalladium-catalyzed allylation with allylstannane or allylsilane, and rhodiumMOP-based phosphine-catalyzed arylation with arylstannanes showed impressive early success. A key concept is catalytic generation of reactive organometal-chiral ligand complexes from corresponding less reactive organometallic reagents in situ. Excellent feature articles have been published on this exciting topic. However, in great contrast to the chiral amino alcohol catalyzed asymmetric alkylation of aldehydes with organozinc reagents, which has become a very effective and general method, the catalytic asymmetric * To whom correspondence should be addressed. Tel: 81-(0)75-753-4553. Fax: 81-(0)75-753-4604. E-mail: tomioka@pharm.kyoto-u.ac.jp. Chem. Rev. 2008, 108, 2874–2886 2874

C2 Symmetric Chiral NHC Ligand for Asymmetric Quaternary Carbon Constructing Copper-Catalyzed Conjugate Addition of Grignard Reagents to 3-Substituted Cyclohexenones

The asymmetric construction of quaternary carbon centers by conjugate addition of Grignard reagents to 3-methyl- and 3-ethylcyclohexenones was realized in a maximum enantioselectivity of 80% by using a C 2 symmetric chiral N-heterocyclic carbene (NHC)-copper catalyst, generated from (4 S,5 S)-1,3-bis(2-methoxyphenyl)-4,5-diphenyl-4,5-dihydro-1 H-imidazol-3-ium tetrafluoroborate and copper(II) triflate. The stereostructures of the NHC-Au complexes were analyzed by X-ray crystallography, which rationalized the good stereocontrolling ability of N-aryl NHCs.

Asymmetric organolithium additions to imines

The reaction of methyllithium with 4-methoxyphenylimine of 1-naphthalenecarbaldehyde (1) in the presence of the chiral ligand A afforded, contrary to 1,4-addition with the cyclohexylimine, the corresponding 1,2-addition product as an optically active amine (2) in 70% ee.

Dimethylzinc-initiated radical reactions.

Developments in modern organic synthesis owe much to the field of radical chemistry. Mild reaction conditions, high selectivity, good functional group tolerance and high product yield are features that have made reactions involving radical species indispensable tools for synthetic chemists. In part, the discovery of new radical initiators has led to the efficiency that now characterizes most radical reactions. This Account describes our investigations of radical reactions initiated by dimethylzinc. In 2001, we unexpectedly observed this reaction while investigating the amidophosphane-copper-catalyzed asymmetric addition of dimethylzinc to N-sulfonyl imines with tetrahydrofuran (THF) as reaction solvent. However, instead of adding the desired methyl group to the N-sulfonyl imine, we produced the THF adduct in excellent yield. This result laid the foundation for our discovery of novel modes of reactivity. Further investigations of the unexpected addition reaction revealed that a trace amount of air was needed for reaction progress, indicating that radical intermediates were involved. Indeed, controlled injection of air into the reaction flask by a syringe pump through a sodium hydroxide tube afforded the products in good to excellent yield. In addition, the reaction proved to be chemoselective for a C=N bond over a C=O bond, as well as for 1,4-addition over 1,2-addition. We developed asymmetric variants of the radical addition reaction of ethers to imines using chiral N-sulfinyl imines to produce the adducts in reasonably high stereoselectivity (up to 11:1). A 93:7 diastereomeric ratio of the adduct was obtained when bis(8-phenylmenthyl) benzylidenemalonate was used in the radical addition of ethers to C=C bonds. Interestingly, in the presence of dimethylzinc and air, arylamines, alkoxyamines, and dialkylhydrazines react with THF to give amino alcohols, oximes, and hydrazones, respectively, in moderate to high yields. We performed a tin-free intermolecular addition of functionalized primary alkyl groups, generated from their corresponding iodides, to N-sulfonyl imines using dimethylzinc, air, boron trifluoride diethyl etherate, and a catalytic amount of copper(II) triflate. Direct C-H bond cleavage from cycloalkanes was also feasible in the presence of dimethylzinc, air, and boron trifluoride diethyl etherate to give the corresponding cycloalkyl radicals, which were suitable nucleophiles for N-sulfonyl imines. In all of the above reactions, dimethylzinc was a superior radical initiator than other conventional initiators such as dibenzoyl peroxide, diethylzinc, and triethylborane. We hope the coming decades will witness the report of other novel radical initiators that would complement the reactivity modes of existing ones.

Asymmetric total synthesis of natural (-)-and unnatural (+)-steganacin : Determination of the absolute configuration of natural antitumor steganacin

Abstract A virtually complete asymmetric control in the synthesis of 2,3-disubstituted butan-4-olide (10) was demonstrated by employing the butenolide (12) as the chiral acceptor for the conjugate 1,4-addition. Highly efficient asymmetric total synthesis of natural (-)- and unnatural (+)-steganacin was accomplished. The absolute stereostructure of natural antitumor steganain was determined to be 1.

Asymmetric conjugate addition reaction by the use of (S)-γ-trityloxymethyl-γ-butyrolactam as a chiral auxiliary

(S)-γ-Trityloxymethyl-γ-butyrolactam (2) serves as a chiral auxiliary in the conjugate addition reaction of the corresponding imide (3) of α,β-unsaturated carboxylic acids with Grignard reagents in the presence of CuBrSMe2 in THF to give, after hydrolysis, the β,β-disubstituted carboxylic acids (5) with predictable absolute configuration and high enantiomeric excess.

Chiral amidomonophosphine-rhodium(I) catalyst for asymmetric 1,4-addition of arylboronic acids to cycloalkenones

Abstract The asymmetric 1,4-addition reaction of arylboronic acids with cycloalkenones was catalyzed by 1 mol% of an amidomonophosphine-rhodium(I) catalyst in a 10:1 mixture of dioxane and water at 100°C, affording 3-arylcycloalkanones in reasonably high enantioselectivity (up to 96% ee) and high yields (up to 99%). The reaction efficacy of phenylboronic acid with cyclohex-2-enone was significantly dependent on the initiation procedure when BINAP was used as a phosphine.

Catalytic asymmetric addition of organolithiums to aldimines

An asymmetric 1,2-addition of organolithiums to imines (1) was catalyzed by a substoichiometric amount (0.05-0.3 equivalent) of a chiral aminoether (2) to provide the corresponding optically active amines (3).

An external chiral ligand controlled enantioselective opening of oxirane and oxetane by organolithiums

Abstract Enantioselective nucleophilic opening reactions of cyclohexene oxide and 3-phenyloxetane were achieved by the combination of an external chiral ligand and organolithiums in the presence of boron trifluoride to give the corresponding alcohols in up to 47% ee.

CATALYTIC ASYMMETRIC CONJUGATE ADDITION OF GRIGNARD REAGENTS MEDIATED BY COPPER(I)-CHIRAL BIDENTATE PHOSPHINE COMPLEX

A catalytic amount of a chiral phosphine 1-copper iodide complex catalyzes the conjugate addition of organomagnesium chlorides to cycloalkenones and pentenolide to give the corresponding addition products in 94-72% ee.